RNAs That Behave Like Prions

Abstract

The term "prion" was originally coined to describe the proteinaceous infectious agents involved in mammalian neurological disorders. More recently, a prion has been defined as a nonchromosomal, protein-based genetic element that is capable of converting the copies of its own benign variant into the prion form, with the new phenotypic effects that can be transmitted through the cytoplasm. Some prions are toxic to the cell, are able to aggregate and/or form amyloid structures, and may be infectious in the wild, but none of those traits are seen as an integral property of all prions. We propose that the definition of prion should be expanded, to include the inducible transmissible entities undergoing autocatalytic conversion and consisting of RNA rather than protein. We show that when seen in this framework, some naturally occurring RNAs, including ribozymes, riboswitches, viroids, viroid-like retroelements, and PIWI-interacting RNAs (piRNAs), possess several of the characteristic properties of prions.

Keywords: piRNA; prions; ribozymes; viroids.

FIG 1

Protein prions and RNAs that may behave like prions. In all panels, the dark blue lines and shapes indicate the benign forms of proteins or RNAs, red lines and shapes indicate the prion forms, solid arrowed lines indicate the direction of the reaction, and broken arrowed lines indicate the autocatalytic cleavages (gray for the relatively inefficient reactions and black for the more efficient ones). (A) A general scheme of protein prion induction and propagation. The benign form of a protein is converted into the prion form only rarely and spontaneously (left), but once formed, it is able to turn more copies of the benign form into the prion form (center), and in many cases to form aggregates in the cell (right). (B) The “Viennese prion.” (C) A putative prion-like derivative of the glmS ribozyme/riboswitch. The GlcN6P-dependent version described in the text is shown. The green letter G indicates the GlcN6P ligand. The engineered ribozyme requires the presence of a ligand for activity but cleaves with reduced efficiency when acting in cis, and with relatively high efficiency when acting in trans. (D) A putative viroid-derived system engineered to possess prion-like properties. The concatemeric plus-strand viroid RNA is transcribed from the integrated DNA copies (black wavy lines). The engineered HHR region within the viroid RNA processes the concatemer into the unit-length viroids with reduced efficiency when acting in cis, and with relatively high efficiency when acting in trans. (E) Prion-like properties of the ping-pong mechanism of piRNA production. The genomic copies of piRNA clusters and evolutionarily related active transposon copies are shown by black wavy lines, and the enzymes from different protein families that process the piRNA precursors into the mature piRNAs are depicted as gemstones of various colors.